The overall objective of this project is to develop a novel drug- delivery method to selectively deliver antimicrobial drugs to tuberculosis-infected macrophages. Macrophages ingest microparticles that have drug covalently attached via a urease-cleavable linker molecule. The presence of urease is specific to the tuberculosis infection, and therefore the drug is delivered only in infected macrophages. The specific aims of the Phase I project are as follows: (1) develop synthetic-organic procedures for incorporation of urease-cleavable bonds into drug-attachment chemistries; (2) determine extracellular release of model compounds (dyes) by purified urease enzyme; (3) establish macrophage and bacteria cultures and determine intracellular release of model compounds in infected and uninfected macrophage cultures. In Phase II, in vivo testing of the microparticle-based drug-delivery technology will be performed. PROPOSED COMMERCIAL APPLICATION: The described drug-delivery technology has the potential to provide significant improvement in the treatment of macrophage-resident diseases such as tuberculosis and HIV. In treatment of these diseases, drug- delivery systems are not available which target the treatment only to infected macrophages.